Several classes of murine leukemia viruses (MLVs) are capable of causing progressive, non-inflammatory neurodegenerative changes in the motor system from the cerebral cortex through the spinal cord upon infection of the central nervous system (CNS). The disease presentations induced by these neurovirulent MLVs are clinically and histopathologically similar to those observed in prion-associated spongiform encephalopathies and amyotrophic lateral sclerosis (ALS). Furthermore, the neurovirulent MLV infections bear a striking resemblance to HIV-associated AIDS dementia in that the major CNS target cells are the microglia, and it is the infection of this cell type that is responsible for the precipitation of motor neuron pathology. Thus, given the similarities with human diseases, the MLV-induced neurodegenerative disease models provide appealing and accessible systems for dissecting complex issues associated with microglial involvement in neurodegeneration at the cellular and molecular levels. While several lines of evidence have clearly established that the infection of microglia by neurovirulent MLVs is the formative event in neurodegeneration, the mechanisms responsible are not yet known. Thus, the overall goal of this grant is to understand how MLV infection of microglia leads to neurodegeneration of motor system neurons. To understand the process we have subdivided the goal into two major areas of inquiry. The first area focuses on the viruses themselves and their expression within microglia and endeavors to ask "What virus features and life cycle events are required for inducing neurodegeneration?" The second area of inquiry asks "How does NV MLV infection of microglia affect their constitutive CNS function?" The expectation is that the insights gained from investigating MLV-microglial interactions will have broad applicability toward understanding the role microglia play in CNS health and disease. [unreadable] [unreadable]